Compounds

ABSTRACT

The invention relates to novel compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.

This invention relates to novel compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.

EPA 0 021 580 and EPA 0 076 072 describe sulphonamide derivatives which are disclosed as having antiarrhythmic activity. A structurally distinct class of compounds has now been discovered, which have been found to have 5HT₆ receptor antagonist activity. 5HT₆ receptor antagonists are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders (including disturbances of Circadian rhythym), feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of utility for cognitive memory enhancement. Compounds of the invention are also expected to be of use in the treatment of certain GI (gastrointestinal) disorders such as IBS (Irritable Bowel Syndrome).

The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof

wherein:

P is phenyl, naphthyl, anthracenyl, a bicyclic heterocyclic ring, a tricyclic heteroaromatic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;

A is a single bond, a C₁₋₆alkylene or a C₁₋₆alkenylene group;

B is SO₂;

R¹ is halogen, C₁₋₆alkyl optionally substituted by one or more fluorine atoms, C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₁₋₆alkynyl, C₁₋₆alkanoyl, C₁₋₆alkoxy, OCF₃, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, nitro, cyano, NR¹⁰R¹¹ where R¹⁰ and R¹¹ are independently hydrogen, C₁₋₆alkyl or optionally substituted phenyl, SR¹¹ where R¹¹ is as defined above or R¹ is optionally substituted phenyl, naphthyl, a bicyclic heterocyclic ring, or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur, or R¹ together with a second R¹ substituent forms a group —O—CH₂—O—, OCH₂CH₂O—, —CH₂CH₂CH— or —CH₂CH₂CH₂CH₂—,

n is 0, 1, 2, 3, 4, 5 or 6;

R² is hydrogen, C₁₋₆ alkyl, arylC₁₋₆ alkyl or together with group P form a 5 to 8 membered ring optionally substituted with one or more C₁₋₆alkyl groups;

R³ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkanoyl, C₁₋₆alkoxy optionally substituted with one or more fluorine atoms, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, nitro, trifluoromethyl, cyano or aryl or together with the group R⁵ forms a group (CH₂)₂O or (CH₂)₃O optionally substituted with 1 or more C₁₋₆alkyl groups;

R⁴ is —X(CH₂)p-R⁶ where X is a single bond, CH₂, O, NH or N-alkyl and p is 0 to 6 and R⁶ is an optionally substituted 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R⁶ is NR⁷R⁸ where R⁷ and R⁸ are independently hydrogen, C₁₋₆ alkyl or aryl C₁₋₆ alkyl; and

R⁵ is a group R³ or together with R³ forms a group (CH₂)₂O or (CH₂)₃O optionally substituted with 1 or more C₁₋₆alkyl groups.

C₁₋₆ Alkyl groups, whether alone or as part of another group, may be straight chain or branched. As used herein the term aryl includes phenyl and naphthyl. When a group is defined as “optionally substituted”, unless otherwise stated, suitable substituents include halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkanoyl, C₁₋₆alkoxy optionally substituted with one or more fluorine atoms, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, nitro, trifluoromethyl, or cyano.

When P is a bicyclic heterocyclic ring, suitable examples include benzothiophene, indole, quinoline or isoquinoline. Bicyclic heterocyclic rings can also be partially saturated. When P is a tricyclic heteroaromatic ring suitable examples include dibenzofuran. Suitable 5 to 7-membered heterocyclic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl. The heterocyclic rings can be linked to the remainder of the molecule via any suitable carbon atom or, when present, a nitrogen atom. Preferably P is phenyl or naphthyl.

Suitably A is a single bond, a methylene or ethylene group or a —CH═CH-group. Preferably A is a single bond or methylene.

When R¹ is a a bicyclic heterocyclic ring or a 5 to 7 membered heterocyclic ring suitable examples include those listed in the definition of P.

It will be appreciated that when R¹ combines with a second R¹ substituent the two substituents must be attached to adjacent atoms on the ring P. Thus, when P is phenyl, groups such as methylenedioxyphenyl, ethylenedioxyphenyl, indane and tetrahydronapthalene are within the scope of this invention.

Suitably R¹ is hydrogen, halogen, phenyl, C₁₋₆alkoxy most preferably OMe, SR¹¹ most preferably SMe or C₁₋₆alkyl optionally substituted by one or more fluorine atoms, for example methyl or trifluoromethyl. Preferably R¹ is halogen. Preferably n is 0, 1, 2, 3 or 4.

Suitably R² is hydrogen, methyl or together with group P form a 5 or 6-membered ring. It will be appreciated that when groups P and R² are linked together the latter must be attached to the adjacent carbon atom on the ring P i.e. with an ortho relationship with respect to group A.

It will be appreciated that when R³/R⁵ groups are linked together the two groups must be attached to adjacent carbon atoms of the phenyl ring. Preferably R³ is a group R⁵, in particular hydrogen.

Preferably R⁴ is meta with respect to the substituent B. Preferably X is a bond, p is 0 and R⁶ is an optionally substituted 5- to 7-membered heterocyclic ring. The heterocyclic rings can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom. Optional substituents for these rings, which can be present on carbon and/or nitrogen atoms, include C₁₋₆alkyl, in particular methyl or NR⁹R¹⁰ where R⁹ and R¹⁰ are independently hydrogen or C₁₋₆alkyl. More preferably R⁴ is an optionally substituted piperazine. Most preferably R⁴ is N-methyl piperazine or NH-piperazine.

Preferably R⁵ is para with respect to the substituent B. Suitably R⁵ is C₁₋₆alkoxy. Preferably R⁵ is methoxy.

Particular compounds of the invention include:

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-naphthalen-1-ylbenzenesulfonamide, N-(4-Chloronaphthalen-1-yl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzene sulfonamide,

N-(3-Bromophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzene sulfonamide,

N-(3,4-Dichlorobenzyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzene sulfonamide,

6-Chloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

1-[4-Methoxy-3-(4-methyl-piperazin-1-yl)-benzene-sulfonyl]-6-trifluoromethyl-2,3 -dihydro-1H-indole,

N-(3-Chlorophenyl)-4-methoxy-N-methyl-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

1-[4-Methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline,

N-(3-Iodo-4-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(5-Iodo-2-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(3,4-Methylenedioxyphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

6-Chloro-1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-5-methyl-2,3-dihydro-1H-indole,

7,8-Dichloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

7,8-Dimethoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

5-Bromo-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

8-Chloro-7-methoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

6,7-Dimethoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-7-phenyl-1,2,3,4-tetrahydroisoquinoline,

8-Bromo-7-methoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

5,6-Dichloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

5,8-Dimethoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

6-Iodo-1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-5-methylthio-2,3-dihydro-1H-indole,

N-(3,4-Dichlorophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(3-Iodophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

6,7,8-Trimethoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

2-[4-Methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-6-pyridin-3-yl-2,3-dihydro-1H-indole,

2-[4-Methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-5-pyridin-3-yl-2,3-dihydro-1H-indole,

1-[4-Methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,5-tetrahydropyrrolo[2,3-f]indole,

1-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline,

N-(3-Bromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide

N-(2-Fluorophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

N-(2-Trifluoromethoxyphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(2-Bromo-4-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(4-Iodophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

N-(9,10-Dioxo-9,10-dihydroanthracen-1-yl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(2-Hydroxymethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(2-methylsulfanylphenyl)-benzenesulfonamide,

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalene-1-yl)-benzenesulfonamide,

N-(2-Ethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

4-Methoxy-N-(2-methylphenyl)-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

N-(3,4-Dimethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

4-Methoxy-N-(2-methoxy-6-methylphenyl)-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(3-Fluoro-5-pyridin-3-ylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

8-Chloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

N-(2-Chloro-4-fluorophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(2-Trifluoromethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-quinolin-7-ylbenzenesulfonamide (E47)

N-(4-Bromophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

N-(3-Bromo-4-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(3-Bromo-2-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

4-Methoxy-N-(2-methoxydibenzofuran-3-yl)-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(4-Cyclohexylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(2-Iodophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

N-(2-Chloro-4-iodophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(2-Bromo-4-fluorophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-[4-(4-Chlorophenyl)thiazol-2-yl]-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

4-Methoxy-N-(3-methylphenyl)-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

N-(3-Ethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

N-(3-Chloro-4-bromophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(2-Acetylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide,

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(4-phenylaminophenyl)-benzenesulfonamide,

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(4-pentyloxyphenyl)-benzenesulfonamide,

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(4-vinylphenyl)benzenesulfonamide,

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(2-pyrrol-1-ylphenyl)-benzenesulfonamide,

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-[4-(4-nitrophenylsulfanyl)phenyl]-benzenesulfonamide,

4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(3-oxazol-5-ylphenyl)-benzenesulfonamide,

N-(4-Bromo-3-trifluoromethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

4-Methoxy-N-(2,3-dimethylphenyl)-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

N-(4-Chloro-3-trifluoromethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide,

1-[4-Methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-5-trifluoromethyl-2,3-dihydro-1H-indole,

7-Bromo-2-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

5,8-Dichloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline,

5,7-Dichloro-1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoline,

1-[4-Methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoline,

1-[4-Methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-6-methyl-1,2,3,4-tetrahydroquinoline,

6-Fluoro-1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoline,

5-Chloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-2,3-dihydro-1H-isoindole hydrochloride,

N-(2-Isopropylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride,

N-(4-Chloronaphthalen-1-yl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

4-Methoxy-N-naphthalen-1-yl-3-piperazin-1-ylbenzenesulfonamide,

N-(3-Chloro-2-methylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-Indan-5-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

4-Methoxy-N-(2-methylsulfanylphenyl)-3-piperazin-1-ylbenzenesulfonamide,

4-Methoxy-3-piperazin-1-yl-N-(2-trifluoromethylphenyl)benzenesulfonamide,

4-Methoxy-N-(2-methylphenyl)-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Ethylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

4-Methoxy-3-piperazin-1-yl-N-(3-trifluoromethylphenyl)benzenesulfonamide,

N-(3,4-Dimethylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Bromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(3,4-Dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(3-Iodophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(3,5-Dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(3-Chlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Chloro-3-fluoro-4-methylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-(4-Chloro-3-methylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-Benzol[1,3 ]dioxol-5-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Bromo-4-methylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2,5-Dibromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2,5-Dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Chloro-4-methylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(4-Bromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Isopropenylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

4-Methoxy-N-(2-methyl-5-nitrophenyl)-3-piperazin-1-ylbenzenesulfonamide,

N-(4-Iodophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(4-tert-Butylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(4-Isopropylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(4-Hexylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2,4-Dibromonaphthalen-1-yl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

4-Methoxy-N-(4-methoxybiphenyl-3-yl)-3-piperazin-1-ylbenzenesulfonamide,

N-(3-Fluoro-5-pyridin-3-ylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

N-Biphenyl-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Benzylphenyl)-4-methoxy-3-piperazin-1 -ylbenzenesulfonamide,

N-(2-Propylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-sec-Butylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-tert-Butylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Butylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(5-Iodo-2-methylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

6-Chloro-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-5-methyl-2,3-dihydro-1H-indole hydrochloride,

6-Iodo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-5-methylsulfanyl-2,3-dihydro-1H-indole,

6-Bromo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroquinoline,

8-Chloro-2-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline,

1-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)-5-methyl-6-trifluoromethyl-2,3-dihydro-1H-indole,

5,8-Dimethoxy-2-(4-methoxy-3-piperazin-1-ylbenzensulfonyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride,

5,8-Dichloro-2-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride,

N-(3-Iodo-4-methylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide,

5,7-Dichloro-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroquinoline,

N-(2-Chloro-3,5-difluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(4-Chloro-2-trifluoromethoxyphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2,4,5-Trichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(5-Chloro-2-methoxyphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(4-Chloro-2-trifluoromethylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(3,5-Dibromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(3-Bromo-2,5-dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2,3,5-Trichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(5-Bromo-2,3-dihydro-benzofuran-7-yl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2-Bromo-3,5-dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(3-Bromo-5,6-dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide,

N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide

N-(2,5-Dibromo-3-chlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide

N-(2,3,5-Tribromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide

6-Iodo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-2,3-dihydro-1H-indole,

5-Iodo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-2,3-dihydro-1H-indole,

7-Bromo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroquinoline

and pharmaceutically acceptable salts thereof.

The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.

Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term ‘compound of formula (I)’ also includes these forms.

Certain compounds of formula (I) are capable of existing, in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the coupling of a compound of formula (II):

in which R¹, R², n, P, and A are as defined in formula (I) or protected derivatives thereof with a compound of formula (III):

in which B, R³, R⁴ and R⁵ are as defined in formula (I) or protected derivatives thereof and L is a leaving, group and optionally thereafter:

removing any protecting groups,

forming a pharmaceutically acceptable salt.

Suitable leaving groups include halogen, in particular chloro. The reaction of a compounds of formulae (II) and (III) is carried out by mixing the two reagents together, optionally in an inert solvent such as dichloromethane with or without the addition of a suitable base such as triethylamine [or pyridine].

Those skilled in the art will appreciate that it may be necessary to protect certain groups. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T. W. ‘Protective groups in organic synthesis’ New York, Wiley (1981).

Compounds of formulae (II) and (III) are commercially available or may be prepared according to known methods or analogous to known methods. For example to prepare compounds of formulae (I) where R³ is H, R⁵ is OMe and R⁴ is 1-piperazine a suitable protecting group in intermediates of formulae (III) was found to be trichloroacetyl. Thus reacting 1-(2-methoxyphenyl) piperazine with trichloroacetyl chloride in a suitable solvent such as dichloromethane in the presence of a base such as diisopropylethylamine afforded 2-(4-trichloroacetyl-piperazin-1-yl) anisole. On treatment with chlorosulfonic acid at 0° C. in a suitable inert solvent such as dichloromethane 3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride was obtained. Coupling of this compound with compounds of formulae (II) as described above followed by treatment with 20% aqueous potassium hydroxide afforded the required compound.

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT₆ receptor antagonist activity and are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders (including disturbances of Circadian rhythym), feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS.

Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.

The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of the above disorders.

The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.

The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.

When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.

The following Descriptions and Examples illustrate the preparation of compounds of the invention.

Description 1 2-(4-Methylpiperazin-1-yl)anisole (D1)

To an ice-cooled, stirred suspension of lithium aluminium hydride (7.9 g, 0.21 mol) in dry tetrahydrofuran (1 50 ml) was added a solution of 1-(2-methoxyphenyl) piperazine (10 g, 52 mmol) in dry tetrahydrofuran (150 ml) over 0.5 h under argon. A solution of ethyl formate (12.6 ml, 0.156 mol) in dry tetrahydrofuran (25 ml) was added to the cold mixture over 0.25 h and the resulting suspension was stirred for a further 2 h at room temperature. Dilute sodium hydroxide solution (15%, 8 ml) was slowly added to the cooled mixture, followed by water (24 ml) and the whole left to stir for 0.25 h. The mixture was filtered and the filtrate concentrated to an oil which was partitioned between dichloromethane and water. The organic phase was dried and concentrated to an oil which was purified by column chromatography on silica gel eluting with a methanol/dichloromethane gradient to afford the title compound as a colourless oil (5.7 g, 53%)

δ_(H) (250 MHz, CDCl₃), 2.36 (3H, s), 2.63 (4H, br s), 3.10 (4H, br s), 3.86 (3H, s), 6.84-7.03 (4H, m).

Description 2 3-(4-Methylpiperazin-1-yl)-4-methoxybenzene sulfonyl chloride (D2)

2-(4-Methylpiperazin-1-yl)anisole (200 mg, 1 mmol) was added in portions over ten minutes to ice-cooled, stirred chlorosulfonic acid (1.2 ml) under argon. The resulting brown solution was stirred at 0° C. for 0.25 h and then at ambient temperature for a further 1.25 h. The solution was slowly poured onto crushed ice (50 g). Dichloromethane (50 ml) was added to the mixture followed by saturated sodium carbonate solution until pH10 was attained in the aqueous phase. The layers were separated and the aqueous phase further extracted with dicholoromethane. The combined organic phases were dried (Na₂SO₄) and concentrated to an oil. The oil was stirred with hexane (4 ml) to give the title compound as a cream solid (210 mg, 71%).

δ_(H) (250 MHz, CDCl₃) 2.43 (3H, s), 2.71 (4H, br t, J=4.2), 3.20 (4H, br t, J=4.2), 4.00 (3H, s), 6.97 (1H, d, J8.7), 7.48 (1H, d, J2.2), 7.72 (1H, dd, J2.2, 8.7), MS: m/z (MH⁺)=305.

Description 3 2-(4-Trichloroacetylpiperazin-1-yl) anisole (D3)

A solution of 1-(2-methoxyphenyl) piperazine (7.0 g) in dichloromethane (30 ml) was added over 0.25 h to a stirred solution of trichloroacetyl chloride (4.06 ml) in dichloromethane (40 ml) at room temperature under argon. Diisopropylethylamine (5.95 ml) was then added and the whole was stirred for 18 h. The reaction mixture was washed with water (2×100 ml), dried (Na₂SO₄) and concentrated to give the title compound (D3) as an oil (11.2 g, 91%). MH⁺337/339.

Description 4 3-(4-Trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride (D4)

A solution of 2-(4-trichloroacetylpiperazin-1-yl) anisole (D3) (10 g) in dichloromethane (115 ml) was added over 0.3 h to ice-cooled chlorosulfonic acid (52 ml). After 0.5 h at 0° C. then 1 h at ambient temperature, the solution was poured onto a mixture of ice-water (500 g) and dichloromethane (500 ml) with rapid stirring. The layers were separated and the organic phase was washed with water (2×800 ml), dried (MgSO₄) and concentrated to give the title compound (D4) as a foam (6.0 g, 46%). MH⁺ 435/437.

Description 5 6-Iodo-2,3-dihydro-1H-indole (D5)

This compound was prepared as previously described (Heterocycles, 1987, 26, 2817)

Description 6 5-Iodo-2,3-dihydro-1H-indole (D6)

This compound was prepared as previously described (Chem. Pharm. Bull. 1987, 35, 3146.)

Description 7 3,5-Dibromoaniline (D7)

A suspension of 3,5-dibromo nitrobenzene (J. Amer. Chem Soc., 1950, 72, 793) (1.0 g, 3.6 mmol) in methanol (30 ml) was added in portions to a stirred mixture of iron powder (0.52 g, 9.3 mmol) in a saturated solution of ammonium chloride (50 ml) at 60° C. The mixture was heated at reflux for 2 h, filtered and the filtrate extracted with dichloromethane (2×70 ml). The organic extract was dried (Na₂SO₄) and concentrated in vacuo to give the title compound (D7) as an oil (0.787 g, 87%), MH⁺ 250/252.

Description 8 2-Bromo-3,5-dichloro-4-nitroaniline (D8)

A solution of N-bromosuccinimide (2.6 g, 14.5 mmol) in N,N-dimethylformamide (DMF) (70 ml) was added over 20 min to a stirred solution of 2,5-dichloro-4-nitroaniline (3.0 g, 14.5 mmol) in DMF (30 ml) at room temperature under argon. After stirring for 18 h, the mixture was poured into water (11) and extracted with dichloromethane (500 ml). The organic extract was washed with water (5×500 ml), dried (MgSO₄) and concentrated to an oil which was purified by column chromatography over silica gel eluting with ethyl acetate/hexane gradient to give the title compound (D8) as a yellow solid (1.0 g, 24%), MH⁺ 285/287.

Description 9 3-Bromo-2,5-dichloro nitrobenzene (D9)

Concentrated sulphuric acid (2.2 ml) was slowly added to a suspension of 2-bromo-3,5-dichloro-4-nitroaniline (D8) (0.9 g, 3.1 mmol) in ethanol (20 ml). The resulting solution was heated to reflux and crushed sodium nitrite (478 mg, 6.9 mmol) was added in two portions. After 0.5 h at reflux, the mixture was cooled, diluted with dichloromethane (50 ml) and saturated sodium hydrogen carbonate solution (50 ml) was added. The layers were separated and the organic phase dried (Na₂SO₄) and concentrated to an oil which was purified by column chromatography over silica gel eluting with a gradient of ethyl acetate/hexane to give the title compound (D9) as an orange solid (0.67 g, 80%), MH⁺ 269/271.

Description 10 3-Bromo-2,5-dichloroaniline (D10)

3-Bromo-2,5-dichloro nitrobenzene (D9) was treated with iron powder in the manner described in Description 7 to give the title compound (D10) as a solid (77%), MH⁺ 240/242.

Description 11 2,3,6-trichloro-4-nitroaniline (D11)

To a suspension of 2,5-dichloro-4-nitroaniline (4.0 g, 19.3 mmol) in ethanol (50 ml) was added concentrated hydrochloric acid (20 ml) and water (20 ml). The mixture was heated to 50° C. and 27.5% hydrogen peroxide (6 ml) added over 15 min. The mixture was maintained at this temperature for a further 2 h, cooled to room temperature, and the solid filtered and washed with water (2×20 ml) to give the title compound (D11) (4.1 g, 88%), MH⁺ 241/243.

Description 12 2,3,5-Trichloro nitrobenzene (D12)

2,3,6-Trichloro-4-nitroaniline (D11) was deaminated as described in Description 9 to give the title compound (D12) (64%), MH⁺ 226/228.

Description 13 2,3,5-Trichloroaniline (D13)

2,3,5-Trichloro nitrobenzene (D12) was reduced with iron powder as described in Description 7 to give the title compound (D13) (68%), MH⁺ 196/198.

Description 14 7-Amino-5-bromo-2,3-dihydrobenzofuran (D14)

Concentrated sulfuric acid (8.8 ml) was added over 5 min to a stirred mixture of 5-bromo-2,3 -dihydrobenzofuran-7-carboxylic acid (0.55 g, 2.3 mmol) in chloroform (27 ml) at 45° C. Sodium azide (0.737 g, 11.3 mmol) was then added portion-wise over 0.5 h and the temperature was maintained for a further 1 h after which time the mixture was poured onto ice (100 g) and extracted with chloroform (2×50 ml). The aqueous phase was basified to pH 12 with 40% sodium hydroxide solution and extracted with chloroform (2×50 ml). The extract was dried (Na₂SO₄), concentrated, and the residue purified by column chromatography over silica gel eluting with a gradient of acetone/toluene to give the title compound (D14) as a solid (63 mg, 13%), MH⁺ 214/216.

Description 15 7-Bromo-1,2,3,4-tetrahydroquinoline (D15)

A solution of 7-bromoquinoline (J. Amer. Chem. Soc., 1947, 69, 705) (362 mg, 1.74 mmol) in glacial acetic acid (10 ml) was treated portion-wise with sodium cyanoborohydride (437 mg, 7.0 mmol) under argon at room temperature. After 18 h at this temperature, the mixture was cooled in an ice bath and to it was added water (35 ml) and 50% aq. sodium hydroxide until pH 14 was attained. The mixture was extracted with dichloromethane and the organic phase washed with saturated sodium chloride solution, dried (Na₂SO₄) and concentrated in vacuo to a residue which was purified by column chromatography over silica gel eluting with a gradient of methanol/dichloromethane to give the title compound (D15) (168 mg, 46%). MH⁺ 212/214.

Description 16 3-(4-Methyl-1-piperazin-1-yl)-4-methoxybenzenesulphonamide (D16)

The title compound (D16) was prepared in 35% yield by treating the sulfonyl chloride (D2) with excess aqueous ammonia in acetone.

Many of the intermediates used in the preparation of the compounds of this invention can be prepared by known procedures. These are shown in Table A.

TABLE A Description No. Compound Name Reference Description 17 6-Trifluoromethyl-2,3- J. Med. Chem. 1998, dihydro-1H-indole (D17) 41(10), 1598-1612 Description 18 6-Chloro-5-methyl-2,3- WO-95/01976 dihydro-1H-indole (D18) Description 19 7,8-Dichloro-1,2,3,4- J. Org. Chem. 1980, tetrahydroisoquinoline 45(10), 1950-3 (D19) Description 20 7,8-Dimethoxy-1,2,3,4- J. Org. Chem. 1968, tetrahydroisoquinoline 33(2), 494-503 (D20) Description 21 5-Bromo-1,2,3,4- WO-95/13274 tetrahydroisoquinoline (D21) Description 22 8-Chloro-7-methoxy- J. Med. Chem. 1982, 1,2,3,4- 25(10), 1235-40 tetrahydroisoquinoline (D22) Description 23 6,7-Dimethoxy-1,2,3,4- J. Org. Chem. 1968, tetrahydroisoquinoline 33(2), 494-503 (D23) Description 24 7-phenyl-1,2,3,4- J. Pharm. Sci. 1970, tetrahydroisoquinoline 59(1), 59-62 (D24) Description 25 8-Bromo-7-methoxy- J. Het. Chem. 1978, 1,2,3,4- 15(3), 429-32 tetrahydroisoquinoline (D25) Description 26 5,6-Dichloro-1,2,3,4- J. Med. Chem. 1980, tetrahydroisoquinoline 25(3), 506-11 (D26) Description 27 5,8-Dimethoxy-1,2,3,4- J. Med. Chem. 1981, tetrahydroisoquinoline 24(12), 1432-7 (D27) Description 28 6-Iodo-5-methylthio-2,3- WO-95/01976 dihydro-1H-indole (D28) Description 29 6,7,8-Trimethoxy- Heterocycles 1989, 29(6), 1,2,3,4- 2817-22 tetrahydroisoquinoline (D29) Description 30 6-pyridin-3-yl-2,3- FR-2530246 dihydro-1H-indole (D30) CA:101:23351 Description 31 5-pyridin-3-yl-2,3- FR-2530246 dihydro-1H-indole (D31) CA:101:23351 Description 32 1,2,3,5- J. Med. Chem. 1996, tetrahydropyrrolo-[2,3- 39(25), 4966-77 ƒ]indole (D32) Description 33 3-Fluoro-5-pyridin-3- WO-96/23783 ylaniline (D33) Description 34 8-Chloro-1,2,3,4- J. Med. Chem. 1980, tetrahydroisoquinoline 23(5), 506-11 (D34) Description 35 5-Trifluoromethyl-2,3- WO-97/48700 dihydro-1H-indole (D35) Description 36 7-Bromo-1,2,3,4- WO-98/06699 tetrahydroisoquinoline (D36) Description 37 5,8-Dichloro-1,2,3,4- J. Med. Chem. 1980, tetrahydroisoquinoline 23(5), 506-11 (D37) Description 38 5,7-Dichloro-1,2,3,4- J. Med. Chem. 1980, tetrahydroquinoline 23(5), 506-11 (D38) Description 39 6-Fluoro-1,2,3,4- JP-55040616 tetrahydroquinoline (D39) Description 40 6-Bromo-1,2,3,4- EP-702004 tetrahydroquinoline (D40) Description 41 8-Chloro-1,2,3,4- J. Med. Chem. 1980, tetrahydroisoquinoline 23(5), 506-11 (D41) Description 42 5-Methyl-6- WO-97/48700 trifluoromethyl-2,3- dihydro-1H-indole (D42) Description 43 5,7-Dichloro-1,2,3,4- JP-55040616 tetrahydroquinoline (D43)

EXAMPLE 1 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-naphthalen-1-ylbenzenesulfonamide hydrochloride (E1)

1-Naphthylamine (29 mg, 0.2 mmol) was added to a stirred solution of 3-(4-methyl-1-piperazinyl)-4-methoxybenzene sulfonyl chloride (D2) (60 mg, 0.2 mmol) in acetone (1 ml) at ambient temperature. After stirring, for 18 h, the precipitate was filtered off and washed with acetone and diethyl ether to afford the title compound (E1) as a cream solid (60 mg, 67%).

δ_(H) (250 MHz, DMSO-d₆) 2.88 (3H,s), 2.90-2.97 (2H, m), 3.15-3.30 (2H, m), 3.37-3.56 (4H, m), 3.89 (3H, s), 7.11 (1H, d J=8.8), 7.22-7.59 (6H, m), 7.86 (1H, d, J=8.3), 7.96 (1H, d, J=9.0), 8.10 (1H, d, J=7.0), 10.18 (1H, s), 10.55 (1H, br s). MS: m/z (MH⁺−HCl)=412.

The compounds in Tables 1 and 2 were prepared in a similar manner to Example 1 using 3-(4-methylpiperazin-1-yl)-4-methoxybenzene sulfonyl chloride (D2) and the appropriate amine. All amines are either commercially available or can be prepared by methods as referenced in Table A above. If required purification by recrystalisation or alternatively by aqueous basic (K₂CO₃) workup followed by column chromatography was carried out.

TABLE 1 MS Compound δ_(H)(250 MHz, DMSO-d6) (MH⁺) N-(4-Chloronaphthalen-1-yl)-4- 2.75(3H, d, J=4.5), 2.70-2.84(2H, 446 methoxy-3-(4-methylpiperazin- m), 3.02-3.15(2H, m), 3.25-3.45(4H, 1-yl)benzene sulfonamide m), 3.74(3H, s), 6.95(1H, d, J=8.5), hydrochloride (E2) 7.07-7.13(2H, m), 7.21(1H, d, J=8.5), 7.48-7.62(3H, m), 8.04(1H, t, J=7.2), 10.11(1H, s), 10.20(1H, br s). N-(3-Bromophenyl)-4-methoxy- 2.68(3H, d J3.5), 2.78-2.88(2H, br 440 3-(4-methylpiperazin-1- m), 3.0-3.10(2H, m), 3.30-3.40(4H, yl)benzene sulfonamide m), 3.71(3H, s), 6.96-7.32(7H, m), hydrochloride (E3) 10.31(1H, s), 10.47(1H, br s). N-(3,4-Dichlorobenzyl)-4- 2.80(3H, s), 3.06-3.55(8H, m), 3.86 444 methoxy-3-(4-methylpiperazin- (3H, s), 4.00(2H, d J=6.4), 7.06 (1H, 1-yl)benzene sulfonamide d, J=8.6), 7.18-7.22(2H, m), 7.35- hydrochloride (E4) 7.40(2H, m), 7.50(1H, d, J=8.3), 8.18(1H, s), 10.83(1H, s). 6-Chloro-2-[4-methoxy-3-(4- 2.68(3H, s), 2.89-3.31 (12H, m), 3.74 436 methylpiperazin-1-yl)- (3H, s), 4.12(2H, t, J=16.5), 7.01- benzenesulfonyl]-1,2,3,4- 7.11(6H, m), 7.38-7.48(2H, m), 9.15 tetrahydroisoquinoline (1H, s), 10.91(1H, s). hydrochloride (E5) 1-[4-Methoxy-3-(4-methyl- 2.64(3H, s), 2.80-3.03(6H, m), 3.20- 456 piperazin-1-yl)-benzene- 3.39(4H, m), 3.68(3H, s), 3.74-3.81 sulfonyl]-6-trifluoromethyl-2,3- (2H, t, J=8.6), 6.95(1H, d, J=2.2), dihydro-1H-indole hydrochloride (E6) 7.02-7.07(1H, d, J=13.0), 7.21-7.22 (2H, d, J=2.1), 7.30-7.35(1H, dd, J=2.2, 8.6), 7.50(1H, s), 10.65(1H, s). N-(3-Chlorophenyl)-4-methoxy- 2.34(3H, s), 2.57(4H, s), 2.97(4H, 410 N-methyl-3-(4-methylpiperazin- s), 3.10(3H, s), 393(3H, s), 6.87- 1-yl)-benzenesulfonamide (E7) 6.90(2H, m), 7.04-7.10(2H, m), 7.18- 7.31(2H,m). 1-[4-Methoxy-3-(4- 1.59-1.69(2H, m), 2.33(3H, s), 2.41- 470 methylpiperazin-1-yl)- 2.52(6H, br s), 2.90(4H, s), 380(2H, benzenesulfonyl]-7- t, J5.7), 3.89(3H, s), 6.83(1H, d, trifluoromethyl-1,2,3,4- J=8.6), 6.94(1H, d J=2.2), 7.06-7.10 tetrahydroquinoline (E8) (1H, d, J=7.9), 7.29(1H, s), 7.35(1H, dd, J=2.3, 8.5), 816(1H, s).

TABLE 2 MS Compound (MH⁺) N-(3-Iodo-4-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 502 benzenesulfonamide hydrochloride (E9) N-(5-Iodo-2-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 502 benzenesulfonamide hydrochloride (E10) N-(3,4-Methylenedioxyphenyl)-4-methoxy-3-(4-methylpiperazin-1- 406 yl)benzenesulfonamide hydrochloride (E11) 6-Chloro-1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-5- 436 methyl-2,3-dihydro-1H-indole (E12) 7,8-Dichloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)- 470/472 benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (E13) 7,8-Dimethoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)- 462 benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (E14) 5-Bromo-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]- 480/482 1,2,3,4-tetrahydroisoquinoline (E15) 8-Chloro-7-methoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)- 466 benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline (E16) 6,7-Dimethoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)- 462 benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (E17) 2-[4-Methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-7-phenyl- 478 1,2,3,4-tetrahydroisoquinoline hydrochloride (E18) 8-Bromo-7-methoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)- 510/512 benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline (E19) 5,6-Dichloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)- 470/472 benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (E20) 5,8-Dimethoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)- 462 benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (E21) 6-Iodo-1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-5- 560 methylthio-2,3-dihydro-1H-indole hydrochloride (E22) N-(3,4-Dichlorophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 430/432 benzenesulfonamide hydrochloride (E23) N-(3-Iodophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 488 benzenesulfonamide hydrochloride (E24) 6,7,8-Trimethoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)- 492 benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline (E25) 2-[4-Methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-6-pyridin- 465 3-yl-2,3-dihydro-1H-indole hydrochloride (E26) 2-[4-Methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-5-pyridin- 465 3-yl-2,3-dihydro-1H-indole hydrochloride (E27) 1-[4-Methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,5- 427 tetrahydropyrrolo[2,3-ƒ]indole hydrochloride (E28) N-(2-Fluorophenyl)-4-methoxy-3-(4-methylpiperazin-1- 380 yl)benzenesulfonamide hydrochloride (E31) N-(2-Trifluoromethoxyphenyl)-4-methoxy-3-(4-methyl piperazin-1-yl)- 446 benzenesulfonamide hydrochloride (E32) N-(2-Bromo-4-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 454/456 benzenesulfonamide hydrochloride (E33) N-(4-Iodophenyl)-4-methoxy-3-(4-methylpiperazin-1- 488 yl)benzenesulfonamide hydrochloride (E34) N-(9,10-Dioxo-9,10-dihydroanthracen-1-yl)-4-methoxy-3-(4- 492 methylpiperazin-1-yl)-benzenesulfonamide hydrochloride (E35) N-(2-Hydroxymethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 392 benzenesulfonamide hydrochloride (E36) 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(2-methylsulfanylphenyl)- 408 benzenesulfonamide hydrochloride (E37) 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(5,6,7,8- 416 tetrahydronaphthalene-1-yl)-benzenesulfonamide hydrochloride (E38) N-(2-Ethylphenyl)-4-methoxy-3-(4-methylpiperazin-1- 390 yl)benzenesulfonamide hydrochloride (E39) 4-Methoxy-N-(2-methylphenyl)-3-(4-methylpiperazin-1- 376 yl)benzenesulfonamide hydrochloride (E40) N-(3,4-Dimethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 390 benzenesulfonamide hydrochloride (E41) 4-Methoxy-N-(2-methoxy-6-methylphenyl)-3-(4-methylpiperazin-1-yl)- 406 benzenesulfonamide hydrochloride (E42) N-(3-Fluoro-5-pyridin-3-ylphenyl)-4-methoxy-3-(4-methylpiperazin-1- 457 yl)-benzenesulfonamide hydrochloride (E43) 8-Chloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]- 436/438 1,2,3,4-tetrahydroisoquinoline hydrochloride (E44) N-(2-Chloro-4-fluorophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 414/416 benzenesulfonamide hydrochloride (E45) N-(2-Trifluorophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 430 benzenesulfonamide hydrochloride (E46) 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-quinolin-7- 413 ylbenzenesulfonamide hydrochloride (E47) N-(4-Bromophenyl)-4-methoxy-3-(4-methylpiperazin-1- 440/442 yl)benzenesulfonamide hydrochloride (E48) N-(3-Bromo-4-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 454/456 benzenesulfonamide hydrochloride (E49) N-(3-Bromo-2-methylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 454/456 benzenesulfonamide hydrochloride (E50) 4-Methoxy-N-(2-methoxydibenzofuran-3-yl)-3-(4-methylpiperazin-1- 482 yl)-benzenesulfonamide hydrochloride (E51) N-(4-Cyclohexylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 444 benzenesulfonamide hydrochloride (E52) N-(2-Iodophenyl)-4-methoxy-3-(4-methylpiperazin-1- 488 yl)benzenesulfonamide hydrochloride (E53) N-(2-Chloro-4-iodophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 522/524 benzenesulfonamide hydrochloride (E54) N-(2-Bromo-4-fluorophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 458/460 benzenesulfonamide hydrochloride (E55) N-[4-(4-Chlorophenyl)thiazol-2-yl]-4-methoxy-3-(4-methylpiperazin-1- 479/481 yl)-benzenesulfonamide hydrochloride (E56) 4-Methoxy-N-(3-methylphenyl)-3-(4-methylpiperazin-1- 376 yl)benzenesulfonamide hydrochloride (E57) N-(3-Ethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide 390 hydrochloride (E58) N-(3-Chloro-4-bromophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)- 474/476 benzenesulfonamide hydrochloride (E59) N-(2-Acetylphenyl)-4-methoxy-3-(4-methylpiperazin-1- 404 yl)benzenesulfonamide hydrochloride (E60) 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(4-phenylaminophenyl) 453 benzenesulfonamide hydrochloride (E61) 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(4-pentyloxyphenyl) 448 benzenesulfonamide hydrochloride (E62) 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(4- 388 vinylphenyl)benzenesulfonamide hydrochloride (E63) 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(2-pyrrol-1-ylphenyl)- 427 benzenesulfonamide hydrochloride (E64) 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-[4-(4- 515 nitrophenylsulfanyl)phenyl]-benzenesulfonamide hydrochloride (E65) 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(3-oxazol-5-ylphenyl)- 429 benzenesulfonamide hydrochloride (E66) N-(4-Bromo-3-trifluoromethylphenyl)-4-methoxy-3-(4- 508/510 methylpiperazin-1-yl)-benzenesulfonamide hydrochloride (E67) 4-Methoxy-N-(2,3-dimethylphenyl)-3-(4-methylpiperazin-1-yl)- 390 benzenesulfonamide hydrochloride (E68) N-(4-Chloro-3-trifluoromethylphenyl)-4-methoxy-3-(4- 464/466 methylpiperazin-1-yl)-benzenesulfonamide hydrochloride (E69) 1-[4-Methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-5- 456 trifluoromethyl-2,3-dihydro-1H-indole hydrochloride (E70) 7-Bromo-2-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4- 480/482 tetrahydroisoquinoline hydrochloride (E71) 5,8-Dichloro-2-[4-methoxy-3-(4-methylpiperazin-1- 470/472 yl)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (E72) 5,7-Dichloro-1-[4-methoxy-3-(4-methylpiperazin-1- 470/472 yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoline hydrochloride (E73) 1-[4-Methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4- 402 tetrahydroquinoline (E75) 1-[4-Methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-6-methyl- 416 1,2,3,4-tetrahydroquinoline (E76) 6-Fluoro-1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]- 434 1,2,3,4-tetrahydroquinoline (E77)

EXAMPLE 78 5-Chloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulphonyl]-2,3-dihydro -1H-isoindole hydrochloride (E78)

Sodium hydride (20 mg of a 60% dispersion in mineral oil, 0.5 mmol) was added to a solution of 3-(4-methyl-1-piperazin-1-yl)-4-methoxybenzenesulphonamide (D16) (53 mg, 0.19 mmol) in DMF (2 ml) in one portion at room temperature under argon. Stirring was continued for 1 hr before a solution of 1,2 bis bromomethyl-4-chlorobenzene (110 mg, 0.37 mmol) in DMF (0.5 ml) was added. The reaction was heated at 60° C. for 3 hrs, cooled and then partitioned between water and dichloromethane. The organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford material which was converted to the title compound by treatment with 1M ethereal HCl. MS: m/z (ME+)=422/424.

EXAMPLE 29 1-(4-Methoxy-3-piperizin-1-ylbenzenesulfonyl)-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline hydrochloride (E29)

A solution of 1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline (E8) (70 mg, 0.15 mmol) and 1-chloro-ethyl chloroformate (0.08 ml, 0.75 mmol) in 1,2-dichloroethane (2 ml) was heated under reflux for 18 h, and then was cooled to ambient temperature. N,N-Diisopropylethylamine (0.05 ml, 0.26 mmol) was added and the resulting solution was heated under reflux for 2 h. The solvent was removed, the residue was dissolved in methanol (4 ml), and the reaction was heated under reflux for 18 h. The solvent was partially removed, dichloromethane (20 ml) was added, and the solution was washed with saturated aqueous sodium hydrogen carbonate (10 ml), dried (MgSO₄), and then evaporated. The residue was purified by column chromatography on silica gel eluting with a methanol-dichloromethane gradient to afford the sulfonamide derivative as a yellowish oil. The oil was dissolved in acetone (0.5 ml) and 1M solution of hydrogen chloride in diethyl ether (0.1 ml) was added. The solution was evaporated, and the residue was coevaporated with dry benzene (3×2 ml) to give the title compound (E25) as a cream solid (38 mg, 52%).

δ_(H) (250 MHz, DMSO-d₆), 1.58 (2H, m), 2.51 (2H, m), 3.01 (4H, br s), 3.16 (4H, br s), 3.79 (2H, t, J=5.80), 3.85 (3H, s), 6.83 (1H, d, J=2.10), 7.13 (1H, d, J=8.74), 7.33 (2H, m), 7.44 (1H, d, J=8.11), 7.95 (1H, s), 9.1 (2H, br s). MS: m/z (MH⁺)=456.

EXAMPLE 30 N-(3-Bromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (E30)

The title compound was prepared using a similar procedure to that of example E29 using N-(3-bromophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide (E3) and 1-chloroethyl chloroformate.

δ_(H) (250 MHz, DMSO-d₆), 2.84 (8H, m), 3.81 (3H, s), 7.01-7.20 (5H, m), 7.23 (1H, m), 7.36 (1H, m). MS: m/z (MH⁺)=426.

EXAMPLE 79 N-(2-Isopropylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride (E79)

Pyridine (0.28 ml) was added to a stirred solution of 2-isopropylaniline (98 mg) and 3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride (D4) (300 mg) in dichloromethane (4 ml) at room temperature. After 18 h the solution was washed with 1M hydrochloric acid (5 ml) then water (5 ml). The organic phase was stirred vigourously with 20% aq. potassium hydroxide (0.5 ml) for 18 h. A 10% aqueous solution of KH₂PO₄ (8 ml) was then added to the mixture and after 0.25 h stirring the layers were separated. The organic layer was dried (Na₂SO₄), acidified with 1M ethereal hydrogen chloride (2 ml) and concentrated to an oil which was stirred with acetone/diethyl ether to afford the title compound (E79) as a white solid (0.224 g, 83%). MH⁺ 390.

The compounds in Table 3 were prepared in a similar manner to Example 79 using 3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride (D4) and the appropriate amine. All amines are either commercially available or can be prepared by methods described above.

TABLE 3 MS Compound (MH⁺) N-(4-Chloronaphthalen-1-yl)-4-methoxy-3-piperazin-1- 432/434 ylbenzenesulfonamide hydrochloride (E80) 4-Methoxy-N-naphthalen-1-yl-3-piperazin-1-ylbenzenesulfonamide 398 hydrochloride (E81) N-(3-Chloro-2-methylphenyl)-4-methoxy-3-piperazin-1- 396/398 ylbenzenesulfonamide hydrochloride (E82) N-Indan-5-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 388 hydrochloride (E83) N-(2-Fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 366 hydrochloride (E84) 4-Methoxy-N-(2-methylsulfanylphenyl)-3-piperazin-1- 394 ylbenzenesulfonamide hydrochloride (E85) 4-Methoxy-3-piperazin-1-yl-N-(2- 416 trifluoromethylphenyl)benzenesulfonamide hydrochloride (E86) 4-Methoxy-N-(2-methylphenyl)-3-piperazin-1-ylbenzenesulfonamide 362 hydrochloride (E87) N-(2-Ethylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 376 hydrochloride (E88) 4-Methoxy-3-piperazin-1-yl-N-(3-trifluoromethylphenyl)benzenesulfonamide 416 hydrochloride (E89) N-(3,4-Dimethylphenyl)-4-methoxy-3-piperazin-1- 376 ylbenzenesulfonamide hydrochloride (E90) N-(2-Bromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 426/428 hydrochloride (E91) N-(3,4-Dichlorophenyl)-4-methoxy-3-piperazin-1- 416/418 ylbenzenesulfonamide hydrochloride E92) N-(3-Iodophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 474 hydrochloride (E93) N-(3,5-Dichlorophenyl)-4-methoxy-3-piperazin-1- 416/418 ylbenzenesulfonamide hydrochloride (E94) N-(3-Chlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 382/384 hydrochloride (E95) N-(2-Chloro-3-fluoro-4-methylphenyl)-4-methoxy-3-piperazin-1-yl- 414/416 benzenesulfonamide hydrochloride (E96) N-(4-Chloro-3-methylphenyl)-4-methoxy-3-piperazin-l- 396/398 ylbenzenesulfonamide hydrochloride (E97) N-Benzol[1,3]dioxol-5-yl-4-methoxy-3-piperazin-1- 392 ylbenzenesulfonamide hydrochloride (E98) N-(2-Bromo-4-methylphenyl)-4-methoxy-3-piperazin-1- 440/442 ylbenzenesulfonamide hydrochloride (E99) N-(2,5-Dibromophenyl)-4-methoxy-3-piperazin-1- 504/506 ylbenzenesulfonamide hydrochloride E100) N-(2,5-Dichlorophenyl)-4-methoxy-3-piperazin-1- 416/418 ylbenzenesulfonamide hydrochloride (E101) N-(2-Chloro-4-methylphenyl)-4-methoxy-3-piperazin-1- 396/398 ylbenzenesulfonamide hydrochloride (E102) N-(4-Bromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 426/428 hydrochloride (E103) N-(2-Isopropenylphenyl)-4-methoxy-3-piperazin-1- 388 ylbenzenesulfonamide hydrochloride (E104) 4-Methoxy-N-(2-methyl-5-nitrophenyl)-3-piperazin-1- 407 ylbenzenesulfonamide hydrochloride (E105) N-(4-Iodophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 474 hydrochloride (E106) N-(4-tert-Butylphenyl)-4-methoxy-3-piperazin-1- 404 ylbenzenesulfonamide hydrochloride (E107) N-(4-Isopropylphenyl)-4-methoxy-3-piperazin-1- 390 ylbenzenesulfonamide hydrochloride (E108) N-(4-Hexylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 432 hydrochloride (E109) N-(2,4-Dibromonaphthalen-1-yl)-4-methoxy-3-piperazin-1- 554/556 ylbenzenesulfonamide hydrochloride (E110) 4-Methoxy-N-(4-methoxybiphenyl-3-yl)-3-piperazin-1- 454 ylbenzenesulfonamide hydrochloride (E111) N-(3-Fluoro-5-pyridin-3-ylphenyl)-4-methoxy-3-piperazin-1-yl- 443 benzenesulfonamide hydrochloride (E112) N-Biphenyl-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 424 hydrochloride (E113) N-(2-Benzylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 438 hydrochloride (E114) N-(2-Propylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 390 hydrochloride (E115) N-(2-sec-Butylphenyl)-4-methoxy-3-piperazin-1- 404 ylbenzenesulfonamide hydrochloride (E116) N-(2-tert-Butylphenyl)-4-methoxy-3-piperazin-1- 404 ylbenzenesulfonamide hydrochloride (E117) N-(2-Butylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide 404 hydrochloride (E118) N-(5-Iodo-2-methylphenyl)-4-methoxy-3-piperazin-1-yl- 488 benzenesulfonamide hydrochloride (E119) N-(2-Chloro-3,5-difluorophenyl)-4-methoxy-3-piperazin-1- 418/420 ylbenzenesulfonamide hydrochloride (E129) N-(4-Chloro-2-trifluoromethoxyphenyl)-4-methoxy-3-piperazin-1- 466/468 ylbenzenesulfonamide hydrochloride (E130) N-(2,4,5-Trichlorophenyl)-4-methoxy-3-piperazin-1- 450/452 ylbenzenesulfonamide hydrochloride (E131) N-(5-Chloro-2-methoxyphenyl)-4-methoxy-3-piperazin-1- 412/414 ylbenzenesulfonamide hydrochloride (E132) N-(4-Chloro-2-trifluoromethylphenyl)-4-methoxy-3-piperazin-1- 450/452 ylbenzenesulfonamide hydrochloride (E133) N-(3,5-Dibromophenyl)-4-methoxy-3-piperazin-1- 506/508 ylbenzenesulfonamide (E134) N-(3-Bromo-2,5-dichlorophenyl)-4-methoxy-3-piperazin-1- 494/496 ylbenzenesulfonamide hydrochloride (E135) N-(2,3,5-Trichlorophenyl)-4-methoxy-3-piperazin-1- 450/452 ylbenzenesulfonamide hydrochloride (E136) N-(5-Bromo-2,3-dihydro-benzofuran-7-yl)-4-methoxy-3-piperazin- 468/470 1-ylbenzenesulfonamide hydrochloride (E137) N-(2-Bromo-3,5-dichlorophenyl)-4-methoxy-3-piperazin-1- ylbenzenesulfonamide (E138) N-(3-Bromo-5,6-dichlorophenyl)-4-methoxy-3-piperazin-1- ylbenzenesulfonamide (E139) N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1- ylbenzenesulfonamide (E140) N-(2,5-Dibromo-3-chlorophenyl)-4-methoxy-3-piperazin-1- ylbenzenesulfonamide (E141) N-(2,3,5-Tribromophenyl)-4-methoxy-3-piperazin-1- ylbenzenesulfonamide (E142)

EXAMPLE 120 6-Chloro-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-5-methyl-2,3-dihydro-1H-indole hydrochloride (E120)

Pyridine (0.28 ml) was added to a stirred solution of 6-chloro-5-methyl-2,3-dihydro-1H-indole (WO-9501976) (0.116 g) and 3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride (D4) (300 mg) in dichioromethane (4 ml) at room temperature. After 18 h the solution was washed with 1M hydrochloric acid (5 ml), water (5 ml), dried (MgSO₄) and concentrated to an oil. The oil was dissolved in 1,4-dioxan (13 ml) and a 0.15 M potassium hydroxide solution (6.5 ml) was added. The solution was stirred at room temperature for 4 h then concentrated to remove the organic solvent, diluted with water (10 ml) and the solution extracted with dichloromethane (20 ml). The organic phase was dried (Na₂SO₄), acidified with 1M ethereal hydrogen chloride (2 ml), concentrated to a solid and stirred with acetone to afford the title compound (0.175 g, 55%). MH⁺ 422/424.

The compounds in Table 4 were prepared in a similar manner to Example 120 usin 3-(4-trichloroacetylpiperazin-1-yl)-4-methoxybenzenesulfonyl chloride (D4) and the appropriate amine. All amines are either commercially available or can be prepared by methods described above.

TABLE 4 MS Compound (MH⁺) 6-Iodo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-5- 546 methylsulfanyl-2,3-dihydro-1H-indole hydrochloride (E121) 6-Bromo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl) 466/468 1,2,3,4-tetrahydroquinoline hydrochloride (E122) 8-Chloro-2-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)- 422/424 1,2,3,4-tetrahydroisoquinoline hydrochloride (E123) 1-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)-5-methyl-6- 456 trifluoromethyl-2,3-dihydro-1H-indole hydrochloride (E124) 6-Iodo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-2,3- 500 dihydro-1H-indole hydrochloride (E143) 5-Iodo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-2,3- 500 dihydro-1H-indole hydrochloride (E144) 7-Bromo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)- 466/468 1,2,3,4-tetrahydroquinoline hydrochloride (E145)

EXAMPLE 125 5,8-Dimethoxy-2-(4-methoxy-3-piperazin-1-ylbenzensulfonyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (E125)

A solution of 1-chloroethylchloroformate (0.12 ml;1.11 mmol) and 5,8-dimethoxy-2-[4-methoxy-3-(4-methyl-1-piperazinyl)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline (E21) (111 mg;0.223 mmol) in 1,2-dichloroethane (3 ml) was refluxed for 0.75 h, cooled, diluted with diisopropylethylamine (0.19 ml;1.11 mmol) and refluxed for a further 2.5 hrs. The solution was concentrated to a residue which was re-dissolved in methanol, refluxed for 1 hr and then stirred at room temperature for 24 h. The mixture was concentrated, and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried, concentrated to a residue and purified by column chromatography on silica gel using a methanol/dichloromethane solvent gradient. The title compound was prepared by dissolving the pure free base material from chromatography in acetone/dichloromethane and acidifying with 1M ethereal HCl (53 mg, 49%). MH⁺456/458.

EXAMPLE 126 5,8-Dichloro-2-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (E126)

The title compound was prepared from its N-methylpiperazine analogue (E72) by a method as described in E125, but the reaction was kept at ambient temperature and the diisopropylethylamine was added at the start of the reaction. MH⁺ 456/458.

EXAMPLE 127 N-(3-Iodo-4-methylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride (E127)

The title compound was prepared from its N-methylpiperazine analogue (E9) by a method as described in E125. MH⁺ 488.

EXAMPLE 128 5,7-Dichloro-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroquinoline hydrochloride (E128)

The title compound was prepared from its N-methylpiperazine analogue (E73) by a method as described in E125. MH⁺ 456/458.

Pharmacological Data

Method for Assay of 5-HT6 Antagonistic Activity

The test compounds were dissolved in polyethylene glycol:dimethyl sulphoxide (1:1) at 1 or 10 mM and diluted to 0.1 mM using 5 mM tris buffer (pH 7.7 @ 25° C.). Dissolution was assisted by addition of 0.02 ml 5M HCl plus heating to 40° C. and sonication for 10 minutes. Serial dilutions of drugs in the same buffer were carried out using either a TECAN 5052 or Biomek 2000 Workstation. Samples of the diluted test compounds (0.05 ml) were mixed with 0.05 ml of radio-ligand [³H]-LSD prepared in the incubation buffer, and 0.4 ml of a suspension of a preparation of the washed membranes of HeLa_(—)5HT6 cells (acquired from Dr. D. Sibley, NIH, Bethesda, see Ref 1)(see Table 1), also in the incubation buffer. The details of the incubation conditions for each assay are shown in Table 2. The incubation buffer was 50 mM Trizma (Sigma, UK) pH7.7 @ 25° C., 4 mM MgCl₂.

After incubation at 37° C., the mixtures were filtered using a Packard Filtermate in Packard TopCount format. Filters were washed with 4×1 ml aliquots of ice-cold incubation buffer. Filters were dried and impregnated with 0.04 ml of Microscint 20 (Packard). IC₅₀ values were estimated from the counts per minute using a four parameter logistic curve fit within EXCEL (2). K_(i) values were calculated using the method of Cheng and Prusoff(3). pIC₅₀ and pK_(i) are the negative log10 of the molar IC₅₀ and K_(i) respectively.

TABLE 1 Details of the methods used to prepare membranes for binding assays 1st Incubation resuspension before final protein conc. in cells/ml in cells/ml spin/resuspension 1,2,3 spin stored aliquots stored aliquots 7 × 10⁷ Yes 20 min at 37° C. 4 mg/ml 1.0 × 10⁸

TABLE 1 Details of the methods used to prepare membranes for binding assays 1st Incubation resuspension before final protein conc. in cells/ml in cells/ml spin/resuspension 1,2,3 spin stored aliquots stored aliquots 7 × 10⁷ Yes 20 min at 37° C. 4 mg/ml 1.0 × 10⁸

REFERENCES

1. MONSMA, F. J., SHEN, Y., WARD, R. P., HAMBLIN, M. W., SIBLEY, D. R. 1993. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol. Pharmacol., 43, 320-327.

2. BOWEN, W. P., JERMAN, J. C. 1995. Nonlinear regression using spreadsheets. Trends in Pharmacol. Sci., 16, 413-417.

3. CHENG, Y. C., PRUSSOF, W. H. 1973. Relationship between inhibition constant (Ki) and the concentration of inhibitor which causes 50% inhibition (IC50) of an enzymatic reaction. Biochem. Pharmacol., 92, 881-894.

All compounds tested showed good selective 5-HT6 receptor antagonist activity, having pKi values 7.5-9.5 at human cloned 5-HT6 receptors. Particularly preferred compounds demonstrated pKi>8.5 and selectivity>100. Examples of such compounds include: 3, 8, 21, 29, 32, 37-39, 41, 44, 45, 53, 54, 57-59, 63, 67, 69, 72, 73, 79, 85, 88, 89, 91,93-95, 100, 104, 107, 113, 117-119, 121-128, 131, 132, 134-143, 145. 

What is claimed is:
 1. A compound of formula (I) or a salt thereof:

wherein: P is phenyl, or naphthyl; A is a single bond, a C₁₋₆alkylene or a C₁₋₆alkenylene group; B is SO₂; R¹ is halogen, C₁₋₆alkyl optionally substituted by one or more fluorine atoms, C₃₋₆cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkanoyl, C₁₋₆alkoxy, OCF₃, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, nitro, cyano, NR¹⁰R¹¹ where R¹⁰ and R¹¹ are independently hydrogen, C₁₋₆alkyl or optionally substituted phenyl, SR¹¹ where R¹¹ is as defined above or R¹ is optionally substituted phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur, or R¹ together with a second R¹ substituent forms a group —O—CH₂—O—, OCH₂CH₂O—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—, n is 0, 1, 2, 3, 4, 5 or 6; R² is hydrogen, C₁₋₆ alkyl, aryl C₁₋₆ alkyl or together with group P form a 5 to 8 membered ring optionally substituted with one or more C₁₋₆alkyl groups; R³ is hydrogen, halogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkanoyl, C₁₋₆alkoxy optionally substituted with one or more fluorine atoms, hydroxy, hydroxyC₁₋₆alkyl, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkoxy, nitro, trifluoromethyl, cyano or aryl or together with the group R⁵ forms a group (CH₂)₂O or (CH₂)₃O optionally substituted with 1 or more C₁₋₆alkyl groups; R⁴ is piperazine, optionally substituted by C1-6alkyl with a meta relationship with the group B; and R⁵ is methoxy with a para relationship to the group B.
 2. A compound according to claim 1 in which R¹ is hydrogen, halogen, C₁₋₆alkoxy or C₁₋₆alkyl optionally substituted by one or more halogen atoms.
 3. A compound according to claim 2 in which R⁵ is methoxy.
 4. A compound according to claim 1 which is: N-(3-Bromophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzene sulfonamide, 1-[4-Methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline, 5,8-Dimethoxy-2-[4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline, 1-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline, N-(2-Trifluoromethoxyphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide, 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(2-methylsulfanylphenyl)-benzenesulfonamide, 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(5,6,7,8-tetrahydronaphthalene-1-yl)-benzenesulfonamide, N-(2-Ethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide, N-(3,4-Dimethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide, 8-Chloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline, N-(2-Chloro-4-fluorophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide, N-(2-Iodophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide, N-(2-Chloro-4-iodophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide, 4-Methoxy-N-(3-methylphenyl)-3-(4-methylpiperazin-1-yl)benzenesulfonamide, N-(3-Ethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonamide, N-(3-Chloro-4-bromophenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide, 4-Methoxy-3-(4-methylpiperazin-1-yl)-N-(4-vinylphenyl)benzenesulfonamide, N-(4-Bromo-3-trifluoromethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide, N-(4-Chloro-3-trifluoromethylphenyl)-4-methoxy-3-(4-methylpiperazin-1-yl)-benzenesulfonamide, 5,8-Dichloro-2-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline, 5,7-Dichloro-1-[4-methoxy-3-(4-methylpiperazin-1-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoline, N-(2-Isopropylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide hydrochloride, 4-Methoxy-N-(2-methylsulfanylphenyl)-3-piperazin-1-ylbenzenesulfonamide, N-(2-Ethylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 4-Methoxy-3-piperazin-1-yl-N-(3-trifluoromethylphenyl)benzenesulfonamide, N-(2-Bromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(3-Iodophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(3,5-Dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(3-Chlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(2,5-Dibromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(2-Isopropenylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(4-tert-Butylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-Biphenyl-2-yl-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(2-tert-Butylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(2-Butylphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(5-Iodo-2-methylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide, 6-Iodo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-5-methylsulfanyl-2,3-dihydro-1H-indole, 6-Bromo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroquinoline, 8-Chloro-2-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline, 1-(4-Methoxy-3-piperazin-1-ylbenzenesulfonyl)-5-methyl-6-trifluoromethyl-2,3-dihydro-1H-indole, 5,8-Dimethoxy-2-(4-methoxy-3-piperazin-1-ylbenzensulfonyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 5,8-Dichloro-2-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, N-(3-Iodo-4-methylphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide, 5,7-Dichloro-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroquinoline, N-(2,4,5-Trichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(5-Chloro-2-methoxyphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(3,5-Dibromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(3-Bromo-2,5-dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(2,3,5-Trichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(5-Bromo-2,3-dihydro-benzofuran-7-yl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(2-Bromo-3,5-dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(3-Bromo-5,6-dichlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(2,5-Dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(2,5-Dibromo-3-chlorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, N-(2,3,5-Tribromophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide, 6-Iodo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-2,3-dihydro-1H-indole, and 7-Bromo-1-(4-methoxy-3-piperazin-1-ylbenzenesulfonyl)-1,2,3,4-tetrahydroquinoline and pharmaceutically acceptable salts thereof.
 5. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.
 6. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the coupling of a compound of formula (II):

in which R¹, R², n, P, and A are as defined in formula (I) or protected derivatives thereof with a compound of formula (III):

in which B, R³, R⁴ and R⁵ are as defined in formula (I) or protected derivatives thereof and L is a leaving group and optionally thereafter removing any protecting groups forming a pharmaceutically acceptable salt.
 7. A method of treating anxiety and/or depression comprising administering to a subject a safe and effective amount of a compound according to claim
 1. 